Gallbladder cancer (GBC), a rare and aggressive malignancy, is substantially less explored than other cancers, and particularly its immune landscape has not been fully characterized. This study proposes to discover immune-related signatures, build a robust prognostic model, and guide immunotherapy for GBC. It performed differential expression analysis on transcriptomic data from TCGA-GBC (RNA-seq) and GSE139902 (microarray) datasets, and found a total of 4,312 and 1,125 significantly differentially expressed genes (DEGs), respectively. Among these, 96 DEGs overlapped with known immune-associated markers. Univariate Cox regression revealed 18 survival-related immune genes, including LAMP3 (HR=1.78, 95% CI: 1.42-2.24, p=1.2E-05). Multivariate analysis refined the model to five immune-related genes: LAMP3 (HR=1.78, 95% CI: 1.42-2.24, p=1.2E-05), IDO1 (HR=1.56, 95% CI: 1.23-1.98, p=2.3E-04), CCL4 (HR=1.45, 95% CI: 1.15-1.83, p=0.0018), CD276 (HR=0.72, 95% CI: 0.56-0.93, p=0.0046), and CXCL8 (HR=1.32, 95% CI: 1.06-1.65, p=0.012), where CD276 was identified as a protective factor.

The model showed robust predictive performance, with AUCs of 0.796, 0.783, and 0.762 for 1-, 3-, and 5-year overall survival in TCGA-GBC, and 0.815, 0.788, and 0.764 in the independent GSE168453 dataset. Furthermore, TIDE and SubMap analysis indicated that high-risk patients had a higher response rate to anti-PD1 therapy (40.2% vs. 29.8%, p<0.05), with high-risk patients more sensitive to anti-CTLA4 and low-risk patients to anti-PD1. Functional enrichment showed these genes are involved in immune checkpoint regulation, antigen processing, and inflammatory response. These findings demonstrate the utility of immune-related gene signatures for prognostic modeling and therapeutic decision-making in GBC.

Tumor microenvironment (TME) is critical in fostering cancer development, and overcoming anti-tumor immunity. In this systematic review, literature on the cellular and molecular mechanisms through which the TME facilitates immune evasion were reviewed through publications until December 2024. A thorough search in PubMed, EMBASE, and Web of Science found 55 pertinent studies. The results indicated that the immunosuppressive cells (regulatory T cells (T-regs), tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs) suppress cytotoxic T-cell-mediated responses. In addition, the soluble mediators, such as transforming growth factor-beta (TGF- 0), vascular endothelial growth factor (VEGF), and interleukin-10 (IL-10), reconfigure the TME to promote tumor survival. These suppressive factors re-programmed or depleted by therapeutic interventions are improved to boost the effectiveness of immune checkpoint inhibitors and adoptive cell therapy. The knowledge on how TME leads to immune evasion is the basis of the new-generation immunotherapies.

This review aims to address the bottleneck of antigen heterogeneity that restricts the efficacy of chimeric antigen receptor (CAR) T cell therapy in solid tumors, with a focus on exploring the epigenetic regulatory mechanisms of CD70—a promising solid tumor target with aberrant overexpression—and developing next-generation CAR-T strategies to overcome CD70 expression heterogeneity. We comprehensively elucidate the epigenetic mechanisms underlying CD70 expression heterogeneity in solid tumors, and verify the core role of EZH2-mediated H3K27me3 modification in silencing CD70 in partial tumor cells and leading to ultra-low CD70 expression undetectable by conventional assays. Meanwhile, we analyze the limitations of conventional CD70-targeted CAR-T cells in solid tumor treatment, and highlight the revolutionary progress of next-generation CAR-T platforms, especially HLA-independent T cell (HIT) receptor technology, which enables the specific recognition and elimination of CD70 ultra-low expressing tumor cells. Additionally, we summarize the current status of preclinical studies and clinical trials of CD70-targeted CAR-T therapies for solid tumors, including efficacy-enhancing strategies such as epigenetic modulation, combined therapy and gene-edited allogeneic CAR-T cells. In conclusion, CD70 is a paradigm-shifting target for solid tumor immunotherapy, and the development of ultra-sensitive next-generation CAR-T platforms represented by HIT receptors has broken through the key obstacle of targeting CD70 ultra-low expressing cells. The integration of epigenetic diagnostic techniques, high-sensitivity CAR-T cells and rational combination therapy strategies will be the key to realizing the curative potential of CD70-targeted therapy, and this therapy is expected to reshape the treatment landscape of CD70-positive solid tumors, while the translation of these technological breakthroughs still faces challenges such as biomarker development, toxicity management and manufacturing scalability that need to be addressed.

The metabolic rivalry in tumor microenvironment (TME) is a unifying site of immune abnormality and treatment resistance in tumor. To support unregulated proliferation, tumor cells reorganise their metabolism, including the use of essential nutrients like glucose, amino acids, and lipids and production of toxic metabolic by-products which damage immune effector functions. This has rendered cytotoxic T lymphocytes (CTLs), natural killer (NK) cells, and dendritic cells to be without the necessary substrates to activate and survive, which results in an immunosuppressive niche. This imbalance is further worsened by hypoxia and acidosis which stabilize hypoxia-inducible factors (HIFs) and induces the expression of immune checkpoint molecules including PD-L1. This means that along with inhibiting antitumor immunity, metabolic restrictions prevent the efficacy of immunotherapies, targeted therapies, and chemotherapeutic agents. This is a systematic review that is dedicated to the evaluation of existing information on the role of metabolic competition as the mechanism underlying immune escape and therapy failure, especially glycolysis, amino acid metabolism, and lipid reprogramming. It also analyses emerging treatments of metabolic immunodeficiency, such as IDO-inhibitors, arginase-inhibitors, and lactate-targeted therapy, as a way of restoring immune capacity and improving treatment response. The metabolic interaction between tumor and immunity has been identified as a promising field of research to overcome resistance and augment clinical outcome in cancer therapy.

Cancer immunotherapies have achieved remarkable clinical success, yet their efficacy remains limited in tumors with low immunogenicity and insufficient antigen presentation within the tumor microenvironment. The absence or dysfunction of conventional type 1 dendritic cells (cDC1s)—the key antigen-presenting cells responsible for priming and sustaining cytotoxic T cell responses—represents a critical barrier to effective antitumor immunity. Recent advances in cellular reprogramming have opened new avenues to address this limitation through in vivo conversion of tumor cells themselves into immunogenic cell types. This review summarizes the current state of in vivo reprogramming strategies aimed at enhancing tumor immunogenicity and T cell-mediated immunity. We focus primarily on the pioneering approach of converting tumor cells into cDC1-like cells through adenoviral delivery of the transcription factors PU.1, IRF8, and BATF3 (PIB). This strategy induces profound remodeling of the tumor microenvironment, recruitment and expansion of polyclonal cytotoxic T cells, formation of tertiary lymphoid structures, and establishment of long-term systemic immunity in preclinical models. We discuss the mechanistic basis of this approach, compare it with alternative reprogramming strategies targeting other immune cell lineages, examine the challenges and limitations for clinical translation, and explore future directions for combination therapies. The ability to transform cancer cells from within into allies that orchestrate antitumor immune responses represents a paradigm shift in cancer immunotherapy with the potential to extend benefits to patients who currently fail to respond to existing treatments.

Tumor microenvironment (TME) has been at the center of defining cancer progression, immune evasion, and cancer response to treatment. The TME is an active network of immune cells and stromal cells, endothelial cells, extracellular matrix and soluble mediators that actively influence tumor behavior, rather than being a passive backdrop. This systematic review discusses the role of the TME in the immune escape induced by cellular immunosuppression (T-regs, TAMs, MDSCs), molecular signaling (cytokines, checkpoint ligands), stromal barriers, hypoxia and metabolic reprogramming. Simultaneously, the TME promotes therapeutic resistance to the immune checkpoint inhibitors, targeted therapies, chemotherapy, and adoptive T-cell therapy by restricting immune cell invasion and causing T-cell exhaustion. A systematic literature review revealed 58 quality publications that report on mechanisms of the TME-based resistance and analyze the imaginative approaches to TME remodelling. It has been demonstrated that immunotherapy with TME components, including VEGF, TGF-b, CSF-1R or metabolic enzymes, is more effective. The most promising ones are combination modalities that prevent immune checkpoints and reprogram the TME at the same time. It is important to know that the TME is a dynamic contributor to immune dysfunction and resistance to create a more robust and tailored cancer therapy.

Objective: To methodically assess the prognostic predictive value of baseline neutrophil-to-lymphocyte ratio (NLR) in cancer patients receiving immune checkpoint inhibitor (ICI) therapy.

Methods: We conducted a systematic search in PubMed, Embase, Cochrane Library, and Web of Science. The search covered studies from each database's founding to December 31, 2024. We included cohort studies or post hoc analyses from randomized controlled trials that assessed the association between baseline NLR (neutrophil-to-lymphocyte ratio) and the prognosis of ICI (immunotherapy) treatment. The Newcastle-Ottawa Scale, a tool for quality assessment of non-randomized studies, was used. Random-effect models combine effect sizes across studies. Subgroup analysis (examining results within subgroups), meta-regression (statistical exploration of heterogeneity), and sensitivity analysis (testing the robustness of the results) were performed.

Results: Sixty-eight studies, including 18,947 patients, were analyzed. Patients with high NLR (neutrophil-to-lymphocyte ratio) had significantly poorer overall survival (OS, time until death from any cause) compared to those with low NLR (combined HR=1.96, 95% CI: 1.74-2.21, P<0.001). They also had worse progression-free survival (PFS, time until disease worsens or patient dies) (combined HR=1.82, 95% CI: 1.63-2.03, P<0.001). The high NLR group showed lower objective response rate (ORR, proportion of patients with tumor shrinkage) and disease control rate (DCR, proportion of patients with tumor response or stable disease), with combined ORs of 0.42 (95% CI: 0.35-0.51) and 0.53 (95% CI: 0.44-0.64). Subgroup analysis (examining results by groups) showed consistent associations across cancer types, treatment lines, and ICI types. The NLR cutoff value (the threshold used to define high vs. low NLR) was the main source of heterogeneity (P=0.009). Sensitivity analysis (testing the effects of excluding certain studies) supported the robustness of the results.

Conclusion: Elevated baseline NLR is an independent predictor of poor prognosis in cancer patients receiving ICI therapy. As a simple, inexpensive biomarker, NLR can help screen populations that may benefit from ICI treatment.